Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1).
Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1).
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长非编码RNA HULC通过上调鞘氨醇激酶1（SPHK1）促进肝癌肿瘤血管生成
DOI：
10.18632/oncotarget.6280
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发表时间：
2016-01-05
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
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作者：
Lu Z;Xiao Z;Liu F;Cui M;Li W;Yang Z;Li J;Ye L;Zhang X
在肝癌中高度上调的RNA(HULC)是一种长的非编码RNA(LncRNA)。我们发现，HULC上调了鞘氨醇激酶1(SPHK1)的表达，SPHK1参与了肿瘤血管生成。肝癌患者血清HULC水平与SPHK1及其产物鞘氨醇-1-磷酸(S1P)水平呈正相关。HULC使肝癌细胞SPHK1表达增加。鸡绒毛膜尿囊膜(CAM)检测显示，si-SPHK1可显著阻断HULC促进的血管生成。机制上，HULC通过转录因子E2F1激活肝癌细胞中SPHK1的启动子。染色质免疫沉淀(ChIP)和凝胶迁移率改变分析(EMSA)进一步表明，E2F1能够与SPHK1启动子中的E2F1元件结合。HULC可增加肝癌细胞中E2F1的表达，且HULC与肝癌组织中E2F1的表达呈正相关。有趣的是，HULC通过互补碱基配对隔离了针对E2F1 mRNA 3‘UTR的miR-107。在功能上，si-SPHK1在体内外显著阻断了HULC促进的肿瘤血管生成。综上所述，我们认为HULC通过miR-107/E2F1/SPHK1信号通路促进肿瘤血管生成。我们的发现为肿瘤血管生成的机制提供了新的见解。
Highly up-regulated in liver cancer (HULC) is a long non-coding RNA (lncRNA). We found that HULC up-regulated sphingosine kinase 1 (SPHK1), which is involved in tumor angiogenesis. Levels of HULC were positively correlated with levels of SPHK1 and its product, sphingosine-1-phosphate (S1P), in patients HCC samples. HULC increased SPHK1 in hepatoma cells. Chicken chorioallantoic membrane (CAM) assays revealed that si-SPHK1 remarkably blocked the HULC-enhanced angiogenesis. Mechanistically, HULC activated the promoter of SPHK1 in hepatoma cells through the transcription factor E2F1. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) further showed that E2F1 was capable of binding to the E2F1 element in the SPHK1 promoter. HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3′UTR, by complementary base pairing. Functionally, si-SPHK1 remarkably abolished the HULC-enhanced tumor angiogenesis in vitro and in vivo. Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.